Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.

中文翻译：

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Lowe 综合征中 OCRL 的碱基编辑校正：ABE 介导的患者来源成纤维细胞的功能挽救

Lowe 综合征是一种罕见的 X 连锁多系统疾病，表现为眼睛、肾脏和中枢神经系统的主要异常，由 OCRL 基因 (NG_008638.1) 突变引起。 OCRL 编码肌醇多磷酸 5-磷酸酶，可催化 PI(4,5)P2 水解为 PI4P。 Lowe综合征尚无有效的靶向治疗方法。在这里，我们展示了一种针对患者成纤维细胞中 Lowe 综合征的新型基因疗法，使用腺嘌呤碱基编辑器 (ABE)，可以有效纠正致病性点突变。我们发现，基于 ABE8e-NG 对 OCRL 基因中含有 R844X 突变的 Lowe 患者来源的成纤维细胞系中的致病突变进行校正，可以在 mRNA 和蛋白质水平上恢复 OCRL 表达。它还可以恢复 OCRL 功能障碍的标志性细胞异常，包括纤毛发生、微管锚定、α-肌动蛋白分布和 F-肌动蛋白网络的缺陷。该研究表明ABE介导的基因治疗是治疗Lowe综合征的一种可行方法，为ABE在目前无法治愈的疾病中的治疗应用奠定了基础。